Bicuspid Aortic Valve Aortopathy Syndrome: A Potentially Familiar Disease

LETTER

Bicuspid Aortic Valve Aortopathy Syndrome: A Potentially Familiar Disease To the Editor: We read with great interest the editorial by Sorrell et al1 on bicuspid aortic valves and aortic disorders, which was recently published in the Journal. It is important to highlight the relevance of this congenital disease, prevalent among 0.5% to 2% of the population, and its association with other congenital defects, ascending aortic aneurysm, and the risk of aortic dissection,1,2 as well as its probable hereditary or familial pattern present in 10% to 30% of bicuspid aortic valve cases. Studies in patients with bicuspid aortic valves have shown a decrease in the elasticity and distension ability of the aortic wall related to a reduced content in fibrillin 1 in the vascular wall, leading to increased production of matrix metalloproteases and alterations of the endogenous inhibitors capable of weakening the extracellular matrix. In patients with bicuspid aortic valves, genetic mutations of matrix metalloprotease-2 have been found that are correlated with high matrix metalloprotease-2 plasma concentrations. Furthermore, several polymorphisms have been found in the matrix metalloprotease-1 promoter that affect protein levels.2,3 These studies and the desire to discover the genetic bases for patients with bicuspid aortic valves and the increase in matrix metalloprotease expression in the aortic wall have led our group to study 90 patients with bicuspid aortic valves and 76 controls with tricuspid aortic valves, analyzing the differences and incidences of diverse polymorphisms (⫺1607 1G/2G, ⫺519 A/G, and ⫺340 T/C) of the matrix metalloprotease-1 promoter region related to the concentrations of the protein. Of patients with bicuspid aortic valves, 48% presented with aortic stenosis, 50% presented with insufficiency, 46% presented with ascending aortic aneurysm, and 8% presented with aortic coarctation. Another 11% have a family history of this disorder, which Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and played a role in writing this manuscript.

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provides support for the hypothesis of family grouping. In addition, we found that the haplotype formed by the combination of the 3 alleles with less reported transcriptional activity (1G/A/C) is significantly lower in patients with bicuspid aortic valves (5%) than in patients with tricuspid aortic valves (12.7%). This association is more pronounced when only male patients are considered. Among those with bicuspid aortic valves, the haplotype 1G/A/T, also weakly active, is less common in individuals with an ascending aortic aneurysm (5.1%) than in patients with tricuspid aortic valves (18%). With these results, we may conclude that patients with bicuspid aortic valves and an ascending aortic aneurysm are less likely to have matrix metalloprotease-1 haplotypes considered as protectors. This is consistent with the higher metalloprotease activity present in these patients, which is associated with the appearance of an ascending aortic aneurysm. Nonetheless, further studies are still needed to reveal all the genetic variables of this disease that are of major interest to clinicians and researchers, and to elucidate its many pathogenic mechanisms that are not yet understood. María Martín, MD, PhDa Juan P. Flórez Muñoz, MDa Irene A. Pichel, MDa Isabel Rodríguez, PhDb a Área del Corazón, Cardiología Bone and Mineral Research Unit Hospital Universitario Central de Asturias Oviedo, Spain b

http://dx.doi.org/10.1016/j.amjmed.2012.05.036

References 1. Sorrell VL, Panczyk E, Alpert J. A new disease: bicuspid aortic valve pathology syndrome. Am J Med. 2012;125:322-323. 2. Wilton E, Bland M, Thompson M, Jahangiri M. Matrix metalloproteinase expression in the ascending aorta and aortic valve. Interact Cardiovasc Thorac Surg. 2008;7:40-41. 3. Tzemos N, Lyseggen E, Silversides C, et al. Endothelial function, carotid-femoral stiffness, and plasma matrix metalloproteinase-2 in men with bicuspid aortic valve and dilated aorta. J Am Coll Cardiol. 2010; 16:55:660-668.